The use of synthetic polymers in medical applications, such as in the repair or regeneration of tissues, in particular cartilage, bone or vasculature, has recently attracted significant interest. However, synthetic polymers, for instance polyethylene glycol (PEG) and polyacrylic polymers are generally not capable of selectively facilitating adhesion of cells or facilitate another biospecific function.
Further, several biomolecules, such as peptides, proteins and glycopolymers are readily denatured by heat, proteases, solvents, material processing conditions and/or the manner in which implants are introduced into the body. It is a challenge to provide compositions of synthetic polymers and such biomolecules, whilst retaining the biomolecules in an active form.
There would be great value in attaching biologically active molecules to polymers. Free radical polymerisation is a common method to create protein-polymer hybrid materials as shown in Van Hest et. al. Advances in Polymer Science 2006, 202, 19-52. This free radical polymerisation can also be performed at lower temperatures than condensation polymerisation thereby reducing the risk of denaturing the proteins or biomolecules which are expensive and synthetically intensive to generate. For example, free radical photopolymerisation is often used to prepare hydrogels.
To prepare such protein polymer hybrids by free radical polymerisation the protein or peptide is normally furnished with one polymerisable group as shown by Hubbel et. al. J. Biomed. Mater. Res. 1998, 39, 266. The technique described in this publication may lead to polymers with network defects since the monofunctional peptide functions as a dangling chain end. The consequences are that there is a risk that the peptide is not effectively incorporated into the network and that the resulting polymer be plasticised, to the extent that mechanical properties of the resulting biomaterial are adversely affected. This adverse effect is particularly pronounced with hydrogels.
In Macromolecules, Volume 39, Number 4 (2006), page 1305-1307, Junmin Zhu et al. describe the synthesis of a polyethylene glycol diacrylate macromer with a cell-adhesive peptide ligand. The macromer is prepared by reacting a hexapeptide attached to the carboxylic acid of diaminopropionic acid with acryloyl-PEG-anhydrous succinamide (Acr-PEG-NHS), thereby forming amide bonds. In particular, if diamino propionic acid is used in a polymer prone to enzymatic or hydrolytic attack then this non natural amino acid could give rise to an undesired side effect.
In the synthetic approach by Zhu, the polymerisable entities are attached to the peptide to make a crosslinking peptide prepolymer. However the present inventors propose a route where the prepolymer can be furnished with one or more reactive groups that will be able to react with a peptide or activated peptide. This allows better control of peptide density along the polymer chain and furthermore the prepolymer can be polymerised to generate a network that can be subsequently furnished with the biomolecules, in particular peptides. This is in particular advantageous, when the polymer processing conditions are aggressive and the peptides are preferably attached at the end of a process, e.g. in the manufacture of a sensor.
It is an object of the invention to provide a novel polymer or article that may serve as an alternative to known polymers respectively articles, in particular for use in a medical application, a sensor, a diagnostic application and/or a drug delivery application.
It is an object of the invention to provide a polymer or article that shows satisfactory biocompatibility in vivo (such a low tendency or no tendency to cause an immune response) and/or that is biodegradable, in particular in vivo. In particular, it is an object to provide a polymer of which the biodegradation rate under in vivo conditions is well controlled.
It is a further object of the invention to provide a method for efficiently introducing one or more biologically active molecules, such as one or more functional peptides, into a polymer having a polymerisable functionality larger than 1.
It is a further object of the invention to provide a polymer with good degradation behaviour, in particular reduced acidity during degradation.
It is a further object of the invention to provide a novel polymer with good mechanical properties such as a good elasticity.
It is a further object to provide a polymer or article that shows selective interaction with a cell tissue or biological fluid to promote, suppress or balance a specific biological response.
It is a further object of the invention to provide a polymer matrix that is suitable for sensing purposes and/or for targeted drug delivery.
It is a further object to provide a novel compound that can be used to prepare a polymer or article.
It is a further object to provide a novel compound, polymer or article, that can be used in vivo, which comprises a biomolecular moiety that is capable of interacting with (autologous) cells or with a specific biochemical component, or that comprises a functional group that can be covalently attach with such biomolecular moiety.
It is a further object of the invention to provide an article comprising a coating based on the polymer which can be used to coat implanted articles
One or more other objects that may be solved in accordance with the present invention will become apparent from the description, below.
It has been found possible to meet one or more objects of the present invention by providing a compound comprising (a) at least two polymerisable moieties, (b) at least one amino acid residue of an amino acid comprising at least two amine groups of which at least two amine groups have formed a carbamate, a thiocarbamate or a carbamide group, and (c) a biomolecular moiety linked directly or via a spacer to the carboxylic acid moiety of the diamino acid residue.
In particular the invention relates to a compound, which is polymerisable, represented by formula I
wherein                G is a residue of a polyfunctional compound having at least n functional groups or a moiety X        each X independently represents a moiety comprising a polymerisable group;        each Y independently represents, O, S or NR;        each R independently represents hydrogen or a group selected from substituted and unsubstituted hydrocarbons which optionally contain one or more heteroatoms, preferably hydrogen or a C1-C20 hydrocarbon, more preferably hydrogen or a C1-C8 alkyl;        L represents a substituted or unsubstituted hydrocarbon which optionally contains one or more heteroatoms.        n is an integer having a value of 1 in case G represents an X and n is at least 2, preferably 2-8, in case G represents a residue of a polyfunctional compound having at least n functional groups;        Z is a biomolecular moiety linked directly or via a spacer to the remainder of the compound.        